Therapeutic benzazapine compounds

ABSTRACT

A method for the treatment of neurological disorders, comprising administering to a mammal in need of such treatment an effective amount of a compound of formula I or of formula II (formulae set out on pages following the Examples), wherein 
     R 1 , R 2 , R 3  and R 4  are independently selected from: 
     hydrogen, 
     (1-3C)perfluoroalkyl, 
     halo, nitro and cyano; 
     R 5  is a (1-5C)alkyl group; 
     or a pharmaceutically acceptable salt thereof. 
     Also provided are compounds and pharmaceutical compositions suitable for the treatment of neurological disorders.

This application is a division of our prior application Ser. No.08/096,795, filed Jul. 23, 1993, now U.S. Pat. No. 5,446,039; which inturn is a division of our prior application Ser. No. 07/816,321, filedDec. 31, 1991, now U.S. Pat. No. 5,254,683, issued Oct. 19, 1993.

This invention relates to benz[b]azepine compounds useful in thetreatment of neurological disorders generally in mammals such as man.More specifically, the compounds are useful in the treatment of strokesand/or other neurodegenerative disorders such as hypoglycemia, cerebralpalsy, transient cerebral ischemic attack, perinatal asphyxia, epilepsy,psychosis, Huntington's chorea, amyotrophic lateral sclerosis,Alzheimer's disease, Parkinson's disease, Olivo-pontocerebellar atrophy,viral-induced neurodegeneration such as in acquired immunodeficiencysyndrome and its associated dementia, anoxia such as from drowning,spinal cord and brain trauma, poisoning by exogenous neurotoxins, andchronic pain, for the prevention of drug and alcohol withdrawalsymptoms, and for the inhibition of tolerance and dependence to opiateanalgesics. The invention particularly relates to novel benz[b]azepinecompounds useful in reducing neurological degeneration such as can beinduced by a stroke and the associated functional impairment which canresult. Treatment using a compound of the invention can be remedial ortherapeutic as by administering a compound following an ischemic eventto mitigate the effects of that event. Treatment can also beprophylactic or prospective by administering a compound in anticipationthat an ischemic event may occur, for example in a patient who is proneto stroke.

It is known that ischemic events can trigger a dramatic increase inextracellular concentrations of the excitatory amino acids glutamate andaspartate which can, in turn, cause prolonged neuronal excitationleading to a massive influx of calcium from extracellular tointracellular sites in brain neural cells. A calcium overload canthereby be created which leads to a cascade of events leading to cellcatabolism and eventually resulting in cell death. TheN-methyl-D-aspartate (NMDA) receptor complex is believed to play asignificant role in the cascade of events leading to cell necrosisfollowing an ischemic event.

The compounds provided by this invention may be useful in a variety ofneurodegenerative disorders because they function as excitatory aminoacid antagonists. They may do so indirectly, via allosteric modulationof the glutamate binding site, specifically by acting as antagonists ofthe strychnine-insensitive glycine receptor on the NMDA receptorcomplex. They may also do so directly, by binding to the glutamate siteitself on the NMDA receptor complex.

According to the invention there is provided a method for the treatmentof neurological disorders, comprising administering to a mammal in needof such treatment an effective amount of a compound of formula I or offormula II (formulae set out, together with other formulae referred toby Roman Numerals, on pages following the Examples), wherein

R¹, R², R³ and R⁴ are independently selected from:

hydrogen,

(1-3C)perfluoroalkyl,

halo, nitro and cyano;

R⁵ is a (1-5C)alkyl group;

or a pharmaceutically acceptable salt thereof.

Thus the present invention also provides a compound of formula I or offormula II (as defined above), or a pharmaceutically acceptable saltthereof, for use in medicine; and in particular for use in the treatmentof neurological disorders.

The invention further provides pharmaceutical compositions for thetreatment of neurological disorders comprising a compound of formula Ior of formula II as defined above, or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable diluent or carrier.

Certain compounds having formula I are known from UK PatentSpecification 1 340 334, and also from Birchall and Rees, Can. J. Chem.,52, 610 (1974). However, novel compounds of this invention include thoseof formula I and formula II wherein R² and R³ are not both(independently) selected from the group consisting of hydrogen andhalogen when R¹ and R⁴ are hydrogen.

While not wishing to be bound by theory, it is believed that compoundsof formula II may be converted to the 3-hydroxy derivatives in vivo, andthat they may accordingly be acting as prodrugs.

In this specification the term "alkyl" includes both straight andbranched chain radicals, but it is to be understood that references toindividual radicals such as "propyl" embrace only the straight chain("normal") radical, branched chain isomers such as "isopropyl" beingreferred to specifically.

"Halo" as used generally herein means fluoro, chloro, bromo, or iodo.

It will be appreciated by those skilled in the art that many of thecompounds disclosed herein can exist and be drawn in various tautomericforms, and all references to any particular structure are understood toinclude the various tautomeric forms thereof.

Particular values of (1-5C)alkyl include methyl, ethyl, propyl,isopropyl, butyl, isobutyl, pentyl, isopentyl, and neopentyl.

Particular values of R¹ -R⁴ as (1-3C)perfluoroalkyl includetrifluoromethyl, pentafluoroethyl, and heptafluoropropyl.

Particular values of R¹ -R⁴ as halo include fluoro, chloro, bromo, andiodo.

More particular values of (1-5C)alkyl include methyl, ethyl, and propyl.

More particular values of R¹ -R⁴ as (1-3C)perfluoroalkyl includetrifluoromethyl and pentafluoroethyl.

More particular values of R¹ -R⁴ as halo include fluoro, chloro, andbromo.

Preferred values of R¹, R², R³, and R⁴ include hydrogen and halo.

Preferred values of (1-5C)alkyl include methyl and ethyl.

More preferred values of R¹ and R³ include hydrogen, fluoro, chloro, andbromo.

More preferred values of R² and R⁴ include hydrogen.

Preferred compounds of the invention include:

8-chloro-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benz[b]azepine;

7-chloro-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benz[b]azepine;

8-bromo-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benz[b]azepine;

8-fluoro-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benz[b]azepine;

6,8-dichloro-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benz[b]-azepine;

6,8-dibromo-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benz[b]-azepine;

6,8-difluoro-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benz[b]-azepine;

and the (1-5C)alkyl enol ethers thereof (i.e., compounds of formula IIwhere R⁵ is (1-5C)alkyl), especially the methyl and ethyl enol ethers.

Benz[b]azepines of formula I can be made by processes which includeprocesses known in the chemical arts for the production of structurallyanalogous compounds. Such processes for the manufacture of abenz[b]azepine of formula I as defined above are provided as furtherfeatures of the invention and are illustrated by the followingprocedures in which the meanings of generic radicals are as given aboveunless otherwise qualified. Such a process can be effected, generally,by reacting a compound of formula II, wherein R⁵ is a (1-5C)alkyl group,such as methyl or ethyl, with a boron trihalide.

If not commercially available, the necessary starting materials for theprocedures such as that described above may be made by procedures whichare selected from standard organic chemical techniques, techniques whichare analogous to the synthesis of known, structurally similar compounds,or techniques which are analogous to the above described procedure orthe procedures described in the examples.

A compound of formula II can be made by reacting a corresponding alkylenol ether of formula III with sodium azide in neattrifluoromethanesulfonic acid or concentrated sulfuric acid (Schmidtreaction) at a temperature of about 0° C. to about room temperature.Trifluoromethanesulfonic acid is preferred in cases where any one ormore of R¹ -R⁴ is halogen. R⁵ is preferably methyl or ethyl tofacilitate the Schmidt reaction.

A methyl enol ether of formula III can be made by reacting acorresponding hydroxy naphthoquinone of formula IV with a correspondingalcohol having the formula R⁵ OH, such as methanol or ethanol, in thepresence of a suitable acid such as anhydrous hydrogen chloride. Hydroxynaphthoquinones of formula IV can be made by oxidizing a correspondingtetralone of formula V or of formula Va. The oxidation can be effectedconveniently as a one-pot process in a suitable solvent such astert-butanol and in the presence of a suitable base such as potassiumtert-butoxide, with oxygen bubbled through the rection mixture. It willalso be appreciated by those skilled in the art that suitable stepwiseor multi-pot variations of the one-pot process can be implemented.

Many tetralones of formula V and/or Va suitable for use in the inventionare either available commercially or can be made by procedures alreadyknown in the art. For example, a 1-tetralone of formula V can be made bycyclizing a corresponding acid of formula VI under acidic conditions,for example with polyphosphoric acid with the application of heat. A2-tetralone of formula Va can be made by ethylene insertion into thecorresponding phenylacetic acid chloride of formula VIa, followed bycyclization, following the general method of Rosowsky et al, J. Org.Chem., 33, 4288 (1968).

Compounds of formula VI can be made by reducing a corresponding ketone,for example, by reducing a compound of formula VII by methods known tothe art, e.g. a Wolff-Kishner reduction for the reduction of carbonylgroups using hydrazine and base.

Compounds of formula VIa can be made by converting a benzylic alcohol offormula VIII (X=OH) to a corresponding benzylic chloride (X=Cl) (e.g.,by reacting with an appropriate reactant such as thionyl chloride),followed by reacting the benzyl chloride thus formed with a suitablealkali metal cyanide (e.g., sodium cyanide) to effect cyanidedisplacement of chloride and thereby form a corresponding benzyliccyanide (X=CN). An acid of formula VIa can be prepared as known in theart by hydrolyzing the benzylic cyanide under acidic conditions.

Alternatively, acids of formula VIa can be formed by brominating atoluene corresponding to formula VIII wherein X=H to form thecorresponding benzylic bromide (X=Br), followed by displacement withcyanide as described above to form acid VIa.

It is noted that many enol ethers of formula III can also be made alongthe lines generally disclosed in S. T. Petri et. al., Org. Syn., 69, 220and in J. M. Heerding and H. W. Moore, J. Org. Chem., 4048-4050, (1991).The synthesis is generally illustrated in Scheme I (set forth on pagesfollowing the Examples) as follows. Organolithium compound 10 can bereacted with semisquarate or semisquaric acid compound 12 to therebyproduce 4-(disubstitutedaryl)-3-alkoxy-4-hydroxy-2-cyclobutenone 14. Itis noted that semisquarate compound 12 can be readily obtained, as setforth in Heerding and Moore, supra, by treatment of a dialkyl squarate(such as diethyl, diisopropyl, or dibutyl squarate, all availablecommercially from Aldrich) with a suitable reducing agent such aslithium tri-tert-butoxyaluminohydride, followed by hydrolysis of theintermediate 13 thereby obtained in aqueous hydrochloric acid. Compound14 can in turn be converted, by heating in a suitable solvent such asxylene, to the hydroquinone 16. Hydroquinone 16 can then be oxidized(e.g. with ferric chloride) to the corresponding naphthoquinone 18. Ifnecessary preparatory to conducting the Schmidt reaction on thenaphthoquinone, naphthoquinone 18 can be transetherified, for examplewith methanolic hydrochloric acid, thereby yielding the methoxynaphthoquinone 20 having formula III.

Examples of suitable pharmaceutically acceptable salts are salts formedwith bases which form a physiologically acceptable cation, such asalkali metal (for example, sodium and potassium), alkaline earth metal,aluminum and ammonium salts, as well as salts made with appropriateorganic bases such as triethylamine, morpholine, piperidine, andtriethanolamine. Care should be taken to avoid metals and/or metalcompositions which may result in a metal catalyzed decomposition of theactive ingredient.

When used to intervene therapeutically following a stroke, abenz[b]azepine of formula I generally is administered as an appropriatepharmaceutical composition which comprises a benz[b]azepine of formula Ias defined hereinbefore together with a pharmaceutically acceptablediluent or carrier, the composition being adapted for the particularroute of administration chosen. Such compositions are provided as afurther feature of the invention. They may be obtained employingconventional procedures and excipients and binders and may be in avariety of dosage forms. For example, they may be in the form oftablets, capsules, solutions or suspensions for oral administration; inthe form of suppositories for rectal administration; and in the form ofsterile solutions or suspensions for administration by intravenous orintramuscular injection or infusion.

The dose of compound of formula I which is administered will necessarilybe varied according to principles well known in the art taking accountof the route of administration, the severity of the ischemic disorder,and the size and age of the patient. In general, a compound of formula Iwill be administered to a warm blooded animal (such as man) so that aneffective dose is received, for example a dose in the range of about 0.1to about 10 mg/kg intravenous body weight.

It will be apparent to those skilled in the art that a compound offormula I can be co-administered with other therapeutic or prophylacticagents and/or medicaments that are not medically incompatible therewith.

The actions of compounds of formula I as antagonists at the glycinereceptor of the NMDA receptor complex can be shown by standard testssuch as the [³ H]-glycine binding assay, by functional assays in vitrosuch as tests for measuring glutamate evoked contractions of the guineapig ileum, and by tests in vivo such as ischemia induced by carotidocclusion in the gerbil model.

In the [³ H]-glycine binding assay, neuronal synaptic membranes areprepared from adult (about 250 g) male Sprague-Dawley rats. Freshlydissected cortices and hippocampi are homogenized in 0.32M sucrose (110mg/mL). Synaptosomes are isolated by centrifuga-tion (1000 xg, 10 min),the supernatant is pelleted (20,000 xg, 20 min) and resuspended indouble-distilled water. The suspension was centrifuged for 20 minutes at8,000 xg. The resulting supernatant and bully coat are washed twice(48,000 xg, 10 mins, resuspension in double-deionized water). The finalpellet is quickly frozen (dry ice/ethanol bath) under double-deionizedwater and stored at -70° C.

On the day of the experiment, thawed synaptic membranes are homogenizedwith a Brinkmann Polytron (™, Brinkmann Instruments, Westbury, N.Y.)tissue homogenizer in 50 mM tris(hydroxymethyl)aminomethane citrate, pH7.1. The membranes are incubated with 0.04% Sufact-AMPS X100 (™, Pierce,Rockford, Ill.) in buffer for 20 minutes at 37° C. and washed six timesby centrifugation (48,000 xg, 10 min) and resuspended in buffer. Thefinal pellet is homogenized at 200 mg wet weight/mL of the buffer forthe binding assay.

For [³ H]-glycine binding at the N-methyl-D-aspartate receptor, 20 nM [³H]-glycine (40-60 Ci/mmol, New England Nuclear, Boston, Mass.) isincubated with the membranes suspended in 50 mM tris(hydroxymethyl)aminomethane citrate, pH 7.1 for 30 minutes at 4° C.Glycine, 1 mM, is used to define the nonspecific binding. Bound [³H]-glycine is isolated from free using a Brandel (Biomedical Researchand Development Laboratories, Gaithersburg, Md.) cell harvester forvacuum filtration over glass fiber filters (Whatman GF/B from Brandel,Gaithersburg, Md.) presoaked in 0.025% polyethylenimine. The samplesretained on the glass fiber filters are rinsed 3 times with a total of2.5 mL ice cold buffer. Radioactivity is estimated by liquidscintillation counting. IC₅₀ values are obtained from a least-squaresregression of a logit-log transformation of the data. Typical IC₅₀values for compounds of the invention are illustrated by the compound ofExample 1 (IC₅₀ =30 nanomolar (nM)), Example 3 (IC₅₀ =97 nM), andExample 1a (IC₅₀ =1.0 micromolar (μM).

For glutamate evoked contractions of the guinea pig ileum, themethodology is as described previously (Luzzi et. al., Br. J.Pharmacol., 95, 1271-1277 (1989). The longitudinal muscle and associatedmyenteric plexus are removed and placed in oxygenated modifiedKrebs-Henseleit solution (118 mM NaCl, 4.7 mM KCl, 2.5 mM CaCl₂, 1.2 mMKH₂ PO₄, 25 mM NaHCO₃, and 11 mM glucose). Tissues are suspended onglass rods in organ baths under a resting tension of 0.5 g. After aninitial depolarization with 80 mM potassium to remove possible blockadeof the NMDA receptor channel complex with magnesium, twitch responsesare evoked with 100 μM glutamate. Isometric mechanical responses arerecorded. Tissues are equilibrated for at least 2 hours prior toaddition of compounds.

A dose response curve for the effect of the unknown on the magnitude ofthe glutamate-evoked contractions is generated. Glutamate-evokedcontractions are generated at 20 minute intervals, with the testcompound added 5 minutes before the glutamate. The magnitude of thecontraction with each dose of the unknown is expressed relative to thecontrol, the third contraction evoked by 100 μM glutamate alone in thesame tissue bath. The IC₅₀ is obtained from a least-squares regressionof a logit-log transformation of the data. Typical IC₅₀ values forcompounds according to the invention are illustrated by the compound ofExample 1 (IC₅₀ =0.11 μM) and Example 3 (IC₅₀ =1.0 μM).

After the last contraction for the dose-response curve, 100 μM glycineis added to the bath 10 minutes after the previous addition ofglutamate. 10 minutes later the estimated IC₅₀ to IC₇₀ dose of the testcompound is added and 10 minutes later glutamate is used to evoke thecontraction. The "glycine reversal" is the ability of glycine to competewith the unknown and to prevent the inhibition previously seen by thedose of the unknown.

When testing in vivo using the gerbil ischemic model, adult femaleMongolian gerbils (50-70 g) are anesthetized with 2 to 3% halothane. Thebilateral common carotid arteries at the neck are exposed and occludedwith microaneurysm clips. After 10 min (unless specified), the clips areremoved and the blood flow through the carotid arteries is restored andthe skin is sutured. Test compounds are administered intraperitoneallyboth pre- and post-occlusion, for example 45 minutes before and 5minutes after occlusion of the carotid arteries. Sham-operated animalsare treated in the same manner except that the arteries are not clamped.Gross behavioral observations along with motor activity are recorded for2 hr on the first (24 hr) day following the occlusion. After 4 days,subjects are sacrificed (decapitation), brains are removed, fixed,sectioned and stained with hematoxylin/eosin and cresyl violet.

The brain sections are rated for neuronal damage in the hippocampususing the following rating scale:

0=undamaged, normal

1=slight damage (up to 25%)--restricted CA1/subiculum border

2=moderate damage (up to 50%)--obvious damage, restricted to less thanhalf of CA1 field

3=marked damage (up to 75%)--involving greater than half of CA1 field

4=damage extending beyond CA1 field

Results can be reported as the percentage of neuroprotection afforded bya particular dose and dosing regimen.

Sections (7 micron) are evaluated from each brain. Occasionally,asymmetrical damage may be noted and the rating assigned is the averagescore of the two sides. The average brain damage rating score for eachgroup is recorded, and the damage scores of the drug treated group arecompared to the vehicle-treated group using Wilcoxcon-Rank Sum test.

Typical values in this test for compounds according to the invention areillustrated by the following results: for the compound of Example 1, 57%neuroprotection (relative to sham-operated control) when dosed twicewith 20 mg/kg body weight intraperitoneally (ip) according to the aboveregimen; 44% neuroprotection when dosed with 30 mg/kg body weight ipthree times at 15, 30, and 45 minutes after induction of ischemia; forthe compound of Example 3, neuroprotection when dosed twice with 30mg/kg body weight ip according to the above regimen; for the compound ofExample 1a, 78% neuroprotection when dosed twice with 20 mg/kg bodyweight ip according to the above regimen.

The invention will now be illustrated by the following non-limitingexamples in which, unless stated otherwise:

(i) temperatures are given in degrees Celsius (°C.); operations werecarried out at room or ambient temperature, that is, at a temperature inthe range of 18°-25° C.;

(ii) evaporation of solvent was carried out using a rotary evaporatorunder reduced pressure (600-4000 pascals; 4.5-30 mm Hg) with a bathtemperature of up to 60° C.;

(iii) flash chromatography was carried out on 40 μM silica gel flashchromatography packing obtained from J. T. Baker; thin layerchromatography (TLC) was carried out on Analtech 0.25 mm silica gel GHLFplates (Art 21521), obtainable from Analtech, Newark, Del., USA;

(iv) in general, the course of reactions was followed by TLC andreaction times are given for illustration only;

(v) melting points are uncorrected and (dec) indicates decomposition;the melting points given are those obtained for the materials preparedas described; polymorphism may result in isolation of materials withdifferent melting points in some preparations;

(vi) all final products were essentially pure by TLC and hadsatisfactory nuclear magnetic resonance (NMR) spectra andmicroanalytical data;

(vii) yields are given for illustration only;

(viii) reduced pressures are given as absolute pressures in Pascals(Pa); other pressures are given as gauge pressures in bars;

(ix) chemical symbols have their usual meanings; the followingabbreviations have also been used: v (volume), w (weight); mp (meltingpoint), L [liter(s)], mL (milliliters), mM (millimoles), g [gram(s)], mg[milligram(s)];

(x) solvent ratios are given in volume: volume (v/v) terms, unlessindicated otherwise; and

(xi) conventional acronyms have been employed such as NMR (nuclearmagnetic resonance), THF (tetrahydrofuran), DMSO (dimethylsulfoxide),DMF (dimethylformamide), TFA (trifluoroacetic acid), and so forth.

EXAMPLE 1 8-Chloro-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benz[b]azepine[Formula I: R¹ =R² =R⁴ =H; R³ =Cl]

8-Chloro-2,5-dihydro-2,5-dioxo-3-methoxy-1H-benz[b]azepine [Formula II:R¹ =R² =R⁴ =H; R³ =Cl; R⁵ =CH₃ ] (0.0789 g, 0.332 mM) was added to asolution of 1.01 mL (1.0M, CH₂ Cl₂) boron tribromide in 1.8 mL drymethylene chloride under nitrogen. The suspension was stirred at roomtemperature for 0.42 hours. The reaction mixture was poured into 7 mL ofsaturated aqueous sodium bicarbonate and stirred for 0.25 hours. Thehomogeneous solution was then adjusted to pH=5 by slow addition ofconcentrated hydrochloric acid. The precipitate was vacuum filtered andwashed with water to give 0.0683 g (92%) of white solid which wasrecrystallized from 5 mL DMF and 1 mL of water. After cooling in an icebath, solid was collected by vacuum filtration, washed with water andvacuum dried at 100° C. and 15 Pa to give 0.056 g (75%) of product; mp308.5-310.5 (dec); NMR (DMSO-d₆, 300 MHz): 11.57 (s,1H, N-- H), 10.86(brs,1H, O-- H), 8.04 (d,1H, J_(ortho) =8.7 Hz), 7.54 (d,1H, J_(meta)=2.0 Hz), 7.31 (dd,1H, J_(ortho) =8.7, J_(meta) 2.0 Hz), 6.41 (s,1H);Analysis for C₁₀ H₆ ClNO₃ : Calculated: C, 53.71; H, 2.70; N, 6.26;Found: C, 53.30; H, 2.74; N, 6.29.

Examples 1a-1e describe and disclose a sequential synthetic route formaking the intermediate used to make the title compound of Example 1.

EXAMPLE 1a (Procedure A)8-Chloro-2,5-dihydro-2,5-dioxo-3-methoxy-1H-benz[b]azepine [Formula II:R¹ =R² =R⁴ =H; R³ =Cl; R⁵ =CH₃ ]

7-Chloro-2-methoxy-1,4-napththoquinone [Formula III: R¹ =R² =R⁴ =H; R³=Cl; R⁵ =CH₃ ] (0.71 g, 3.2 mM) was added to 4.1 mL of concentratedsulfuric acid chilled in an ice bath. The cold red solution was stirredunder nitrogen and sodium azide added (0.23 g. 3.5 mM). The reactionmixture was maintained in an ice bath for 0.33 hours then allowed towarm to room temperature and maintained thus for 18 hours. The reactionmixture was recooled in an ice bath and an additional portion of sodiumazide added (0.21 g, 3.2 mM). After 0.33 hours the mixture was allowedto warm to room temperature for 20 hours. Once again the mixture wascooled in an ice bath and sodium azide added (0.21 g, 3.2 mM); themixture was maintained in an ice bath for 0.33 hours and then roomtemperature for 68 hours. The reaction mixture was then poured into 200mL of ice cold saturated aqueous sodium bicarbonate. The resultingprecipitate was filtered off, washed with water to give after vacuumdrying (25° C., 15 Pa) 0.343 g (45%) of dark solid. The solid wasrecystallized from 3 mL DMF and 1 mL of water to give 0.2 g (26%) ofwhite solid; NMR(DMSO-d₆, 250 MHz): 11.39(s,1H, N-- H), 7.93(d,1H,J_(ortho) =8.8 Hz), 7.47(d,1H, J_(meta) =1.7 Hz), 7.28(dd,1H, J_(ortho)=8.8 Hz, J_(meta) =1.7 Hz) 6.35(s,1H), 3.80(s,3H).

EXAMPLE 1a (Procedure B)8-Chloro-2,5-dihydro-2,5-dioxo-3-methoxy-1H-benz[b]azepine [Formula II;R¹ =R² =R⁴ =H; R³ =Cl; R⁵ =CH₃ ]

7-Chloro-2-methoxy-1,4-naphthoquinone [Formula III: R¹ =R² =R⁴ =H; R³=Cl; R⁵ =CH₃ ] (14.74 g, 66.2 mM) was added to trifluoromethanesulfonicacid (153 mL) chilled in an ice bath under nitrogen. The solution wasstirred under nitrogen and sodium azide added (4.74 g, 73.0 mM). Thereaction mixture was maintained in an ice bath for 0.33 hours thenallowed to warm to room temperature and maintained thus for 90 hours.The reaction mixture was recooled in an ice bath and an additionalportion of sodium ozide added (2.15 g, 33.1 mM). After 0.08 hours themixture was allowed to warm to room temperature for 19 hours. Thereaction mixture was then poured into ice cold aqueous sodiumbicarbonate (153 g, 1.82M in 2.3 L). The resulting precipitate wasfiltered off, washed with water to give after vacuum drying (25° C., 15Pa) 13.83 g of tan solid. The solid was recrystallized from 300 mL ofhot DMF. After cooling in an ice bath, the solid was filtered off,washed with cold DMF followed by water to give after vacuum drying (25°C., 15 Pa) 8.12 (52%) of light tan solid; mp 340-342 (dec).

Analysis for C₁₁ H₈ ClNO₃ : Calculated: C, 55.60; H, 3.39; N, 5.89;Found: C, 55.35; H, 3.38; N, 6.07.

EXAMPLE 1b 7-Chloro-2-methoxy-1,4-naphthoquinone [Formula III: R¹ =R²=R⁴ =H; R³ =Cl; R⁵ =CH₃ ]

7-Chloro-2-hydroxy-1,4-naphthoquinone [Formula III: R¹ =R² =R⁴ =R⁵ =H;R³ =Cl] (0.73 g, 3.5 mM) was added to 14 mL of 4% (w/w) hydrogenchloride in methanol under nitrogen at room temperature. The solutionwas heated to reflux temperature for 0.5 hours. Upon cooling to roomtemperature, a precipitate formed which was filtered off and washed withmethanol. After vacuum drying (25° C., 15 Pa) 0.72 g (92%) of orangesolid was obtained; NMR(DMSO-d₆, 250 MHz) 8.10(d,1H, J_(meta) =2.2 Hz)8.04(d.1H, J_(ortho) =8.3 Hz), 7.71(dd,1H, J_(ortho) =8.3, J_(meta) =2.2Hz), 6.19(s,1H), 3.92(s,3H).

EXAMPLE 1c 7-Chloro-2-hydroxy-1,4-naphthoquinone [Formula IV: R¹ =R² =R⁴=H; R³ =Cl]

7-chloro-1-tetralone [Formula V; R¹ =R² =R⁴ =H; R³ =Cl] (27.56 g, 0.153mole) dissolved in 445 mL dry tert-butanol was added over a one hourperiod to a solution of freshly sublimed potassium tert-butoxide (102.7g, 0.916 mole) in 1.15 L of dry tert-butanol saturated with oxygen atroom temperature. Oxygen was bubbled through the solution for two hoursafter completion of the addition. The mixture was poured into stirredice cold hydrochloric acid (1.9 L, 2N) and extracted with diethyl ether.The ethereal extracts were concentrated in vacuo to give a yellow solidwhich was triturated with ethyl acetate. The solid was filtered off,washed with water and vacuum dried (25° C., 15 Pa) 10.5 g of yellowsolid was then taken up in 0.5 L of hot ethyl acetate and the solutionconcentrated to 50 mL. Crystallization was initiated by cooling thesolution in an ice bath. The solid was filtered off, washed with coldethyl acetate and hexane. After vacuum drying, (25° C., 15 Pa), 7.10 g(22%) of yellow plates were obtained; mp 215°-216.5° C.

1-tetralones were prepared by the method of Newman and Seshadri, (M. S.Newman and S. Seshadri, J. Org. Chem., 27, 76 (1962). 2-tetralones wereprepared by the method of Rosowsky et al, J. Org. Chem., 33, 4288(1968). 5,7-dibromo-2-tetralone was prepared using 3,5-dibromobenzylbromide prepared in the following way.

3,5-Dibromobenzyl Bromide

3,5-dibromotoluene (78.92 g, 0.316 mole) was dissolved in 1.27 L ofcarbon tetrachloride; to this solution was added N-bromosuccinimide(61.65 g, 0.346 mole) at room temperature. A portion of dibenzoylperoxide (0.6 g, 0.008 equivalents) was added and the solution heated toreflux temperature for 2.5 hours. The reaction mixture was cooled toroom temperature, filtered and the solvent removed in vacuo to yield asolid. The solid was dissolved in 200 mL of warm hexane, filtered andcooled to room temperature. Crystallizations ensued; the crystals werefiltered off and washed with cold hexane and air dried to give 45.15 g(44%) of 3,5-dibromobenzyl bromide. ¹ H-NMR(CDCl₃); δ7.6 (1H), 7.47(2H), 4.36 (2H).

EXAMPLE 1d 7-Chloro-1-tetralone [Formula V: R¹ =R² =R⁴ =H; R³ =Cl]

4-Chlorophenylbutyric acid [Formula VI: R¹ =R² =R⁴ =H; R³ =Cl] (26.62 g,134.0 mM) was added to 150 g of hot polyphosphoric acid (90° C.); themixture was maintained at 90°-95° C. for 0.33 hours. After cooling toroom temperature, the reaction mixture was added to 400 mL of ice coldstirred water. The solution was allowed to warm to room temperature anddeposited a precipitate. The solid was filtered off, washed with waterand air dried to give 22.3 g (92%) of pale yellow solid. The solid wasrecrystallized from 50 mL of toluene at -10° C. The crystals werecollected and washed with cold toluene and then hexanes to give 18.18 g(75%) of pale yellow crystals; mp 100.3°-101.1° C.

EXAMPLE 1e 4-Chlorophenylbutyric Acid [Formula VI: R¹ =R² =R⁴ =H; R³=Cl]

4-Chlorobenzoyl propionic acid [Formula VII: R¹ =R² =R⁴ =H; R³ =Cl](49.94 g, 234.9 mM) was dissolved under nitrogen in 320 mL oftriethylene glycol. To the stirred room temperature solution was addedpotassium hydroxide (44.5 g, 794 mM) followed by 98% hydrazine hydrate(29.0 g, 580.0 mM). The mixture was heated to reflux temperature (142°C.) for 2 hours. Water and hydrazine hydrate were distilled off atatmospheric pressure; the pot temperature rose to 195°-200° C. After 0.5hours at 195°-200° C., the mixture was cooled to ambient temperature anddiluted with 320 mL of water. The aqueous solution was poured intohydrochloric acid (200 mL, 6N) and further diluted with 200 mL of icewater. Upon standing a solid formed which was filtered off, washed withwater and vacuum dried (25° C., 15 Pa) to render 43.61 g (93%) of whitesolid.

EXAMPLES 2-6

A series of 2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benz[b]azepines offormula I was made according to procedures analogous to those presentedin Example 1. Table I identifies each such compound by naming eachindividual substituent R^(i) ("i" means an integer corresponding to asubstituent designation in the formulae) and presents CHN analyticaldata and melting points for each. Table II also identifies each of thecompounds synthesized and presents NMR data.

EXAMPLES 2a-6a

Examples 2a-6a correspond to intermediate methyl ethers of formula IIused to make each of the corresponding compounds of Examples 2-6; TableIII identifies each of the intermediates and presents ¹ H-NMR data. Eachof the methyl ethers was made according to procedures analogous to thoseset forth in Example 1a, Procedure A or in Example 1a, Procedure B. Theprocedure employed for each intermediate is noted in Table III.

EXAMPLES 2b-6b

Examples 2b-6b correspond to the series of 2-methoxy-1,4-naphtoquinonesof formula III used to make each of the corresponding intermediatemethyl ethers of Examples 2a-6a; Table IV identifies each such compoundand presents NMR data.

EXAMPLE 2c

Example 2c (Table V) identifies the6-chloro-2-hydroxy-1,4-naphthoquinone used to make the corresponding6-chloro methyl ether of Example 2b. The compound was made by astraightforward application of the method J. M. Lyons and R. H. Thomson,J. Chem. Soc., 1953, 2910-2915. It is noted that Lyons and Thomsonreported making a different isomer in their paper, but it is belivedthat the original assignment they reported was is error.

EXAMPLES 3c-6c

Examples 3c-6c correspond to the series of 2-hydroxy-1,4-naphthoquinonesof formula IV used to make each of the corresponding methyl ethers ofExamples 3b-6b; Table V identifies each such compound and presents NMRdata.

EXAMPLES 3d-4d

Examples 3d-4d correspond to the series of 1-tetralones used to make thecorresponding 2-hydroxy-1,4-naphthoquinones of Examples 3c-4c; Table VIidentifies each compound and presents NMR data.

EXAMPLES 5d-6d

Examples 5d-6d correspond to the series of 2-tetralones of formula Vaused to make the corresponding 2-hydroxy-1,4-naphthoquinones of Examples3c-4c; Table VII identifies each compound and presents NMR data.

EXAMPLES 7

The synthetic sequence to make the title compound of Example 7 (compoundidentified and data set forth in Table I and Table II) proceeded viaScheme I (R¹ =R³ =F; R² =R⁴ =H; R⁵ =isopropoxy), and is describedfollowing:

5,7-Difluoro-2-methoxy-1,4-naphthoquinone (Compound 20)

A solution of 0.48 g (13.2 mM) of anhydrous hydrogen chloride in 15 mLof methanol was treated with 0.175 g (0.694 mM) of5,7-difluoro-2-isopropoxy-1,4-naphthoquinone. The mixture was heated tosolvent reflux temperature for 0.33 hours, cooled to room temperatureand concentrated in vacuo to give 0.13 g of product. ¹ H NMR (dmso-d₆):δ=7.8 (m, 1H), 7.68 (dd, 1H, J_(H-Fortho) =7.5 Hz), 6.31 (s, 1H),3.86(s, 3H).

5,7-Difluoro-2-isopropoxy-1,4-naphthoquinone (Compound 18)

A solution of 0.55 g (2.1 mM) of5,7-difluoro-1,4-dihydroxy-2-isopropoxy-naphthalene in 20 mL of diethylether was added over 0.05 hours to a stirred, room temperature solutionof 4.05 g (25 mM) of ferric chloride in 46 mL of water and 12 mL ofisopropanol. The mixture was stirred for 0.75 hours and then extractedwith ethyl acetate. The organic extracts were dried with sodium sulfate,filtered and concentrated to give 0.44 g of tan solid which wasrecrystalized from 3 mL of warm acetic acid and a few drops of water.After cooling to room temperature, the solid was filtered off, washedwith acetonitrile and then water before vacuum drying at roomtemperature to give 0.057 g of yellow solid. mp 172.0°-173.2°; ¹ H NMR(CDCl₃): δ=7.68 (dd, 1H), 7.15 (m, 1H), 6.09 (s, 1H), 4.55 (m, 1H),1.45(d, 6H).

5,7-Difluoro-1,4-dihydroxy-2-isopropoxy-naphthalene (Compound 16)

The THF solution of2-hydroxy-3-isopropoxy-2-(3,5-difluorophenyl)-3-cyclobutenone, videinfra, was diluted with 40 mL of p-xylene and then concentrated to 16mL. The p-xylene solution was then diluted to a total volume of 40 mLwith additional p-xylene and heated under argon to reflux temperaturefor 0.42 hours. The solvent was removed in vacuo to yield 0.87 g ofamber oil. MS(CI, CH₄): m/e=255 (M⁺ +1, base peak).

2-Hydroxy-3-isopropoxy-2-(3,5-difluorophenyl)-3-cyclobutenone (Compound14)

0.753 g (3.9 mM) of 3,5-difluorobromobenzene in 24 mL of dry, distilledTHF was cooled under argon to -75° and 2.34 mL of n-butyllithium (1.54Min hexane) added over 0.033 hours. The mixture was kept at -75° to -70°for 0.42 hours and then transferred via cannula to a -75° solution of0.46 g (3.3 mM) of 3-isopropoxy-3-cyclobutene-1,2-dione in 60 mL of dry,distilled THF over 0.17 hours. The solution was kept at -75° for 0.33hours at which time 1.4 mL of water was added and stirring continued for0.17 hours. The reaction solution was poured into a mixture of crushedice and diethyl ether. The phases were separated and the aqueous phaseextracted with additional diethyl ether. The combined organic extractswere dried over sodium sulfate, filtered and concentrated to give a THFsolution of the product. MS(CI,CH₄): m/e=255 (M⁺ +1, base peak).

3-Isopropoxy73-cyclobutene-1,2-dione (Compound 12)

7.38 g (36.9 mM) of 2,3-diisopropoxy-4-hydroxy-2-cyclobutenone in 116 mLof methylene chloride was stirred with 2 mL of concentrated hydrochloricacid at room temperature for 1 hour. The solution was neutralized anddried over potassium carbonate and sodium sulfate, filtered andconcentrated in vacuo to give 5.14 g of red oil. The oil was flashchromatographed on SiO₂ (7.5 cm diameter×10 cm column) using diethylether--hexane (1:1) as eluant. Concentration of the major fraction gave4.14 g (80%) of yellow oil. ¹ H NMR (CDCl₃): δ=8.48 (s,1H), 5.02 (m,1H), 1.49 (d, 6H); MS(CI, CH₄): m/e=141 (M⁺ +1), 99 (base peak).

2,3-Diisopropoxy-4-hydroxy-2-cyclobutenone (Compound 13)

A solution of 10.02 g (50.55 mM) of3,4-diisopropoxy-3-cyclobutene-1,2-dione in 100 mL of dry, distilled THFwas cooled to -10° and was treated over 0.66 hours with a solution of16.0 g (63.1 mM) of lithium tri-(tert-butoxy)aluminum hydride in 63 mLof dry, distilled THF, while maintaining a -5° to -10° internaltemperature. The temperature was maintained at -5° for an additional 0.5hours. To a stirred, saturated aqueous solution of potassium sodiumtartrate and 50 mL of diethyl ether was added the reaction mixture. Theorganic layer was separated and the aqueous phase extracted with diethylether. The combined extracts were dried over sodium sulfate, filteredand concentrated in vacuo to give 8.12 g of yellow oil. The oil wasflash chromatographed on SiO₂ (7 cm diameter×8.5 cm column) usingdiethyl ether/hexane (1:1) as eluant. Concentration of the majorfraction gave 7.38 g (73%) of colorless oil. ¹ H NMR (CDCl₃): δ=4.9 (m,3H), 2.65 (bs, 1H), 1.42 (d, 6H), 1.30 (m, 6H); MS(CI, CH₄): m/e=201 (M⁺+1),159 (base peak).

EXAMPLE 8

The following illustrate representative pharmaceutical dosage formscontaining a compound of formula I or of formula II, for example asillustrated in any of the previous Examples, (hereafter referred to as"Compound X"), for therapeutic or prophylactic use in humans:

    ______________________________________                                                                mg/tablet                                             ______________________________________                                        (a) Tablet                                                                    Compound X                50.0                                                Mannitol, USP             223.75                                              Croscarmellose sodium     6.0                                                 Maize starch              15.0                                                Hydroxypropylmethylcellulose (HPMC), USP                                                                2.25                                                Magnesium stearate        3.0                                                 (b) Capsule)                                                                  Compound X                10.0                                                Mannitol, USP             488.5                                               Croscarmellose sodium     15.0                                                Magnesium stearate        1.5                                                 ______________________________________                                    

The above formulations may be obtained by conventional procedures wellknown in the pharmaceutical art. The tablets may be enteric coated byconventional means, for example to provide a coating of celluloseacetate phthalate.

EXAMPLE 9

The following is a description of an injectable formulation made withthe compound of Example 1.

A series of aqueous solutions of varying concentrations of the compoundof Example 1 (the "Compound") were made. An aqueous solution formulationsuitable for intravenous administration containing 3.5 mg/mL of theCompound was made by (1) dissolving Meglumine (N-methylglucamine) inwater in an amount sufficient to make a 19.5 mg/mL solution; (2)dissolving the Compound in the solution in an amount sufficient toachieve the desired concentration of Compound of 3.5 mg/mL; and (3)adding sodium chloride or dextrose in an amount sufficient to achieveisotonicity. Concentrations of drug less than 3.5 mg/mL were also made.The formulations were manufactured using typical manufacturingprocedures for parenteral products, for example by using sonication asrequired to help effect dissolution of the Compound.

                                      TABLE I                                     __________________________________________________________________________    Analytical Data and Melting Points for 2,5-dihydro-2,5-dioxo-3-hydroxy-1H-    benz[b]                                                                       azepines (Formula I)                                                          Ex. No.                                                                            R.sup.i =   mp     Formula   C  H  N                                     __________________________________________________________________________    2    R.sup.1 =R.sup.3 =R.sup.4 =H; R.sup.2 =Cl                                                 278    C.sub.10 H.sub.6 ClNO.sub.3                                                          cal                                                                              53.71                                                                            2.70                                                                             6.26                                                                 fnd                                                                              53.51                                                                            2.93                                                                             6.57                                  3    R.sup.1 =R.sup.2 =R.sup.4 =H; R.sup.3 =Br                                                 182-186                                                                              C.sub.10 H.sub.6 BrNO.sub.3                                                          cal                                                                              46.84                                                                            2.86                                                                             4.97                                                                 fnd                                                                              47.21                                                                            2.65                                                                             5.31                                  4    R.sup.1 =R.sup.2 =R.sup.4 =H; R.sup.3 =F                                                  201-203                                                                              C.sub.10 H.sub.6 FNO.sub.3                                                           cal                                                                              57.98                                                                            2.92                                                                             6.76                                                                 fnd                                                                              57.62                                                                            2.89                                                                             6.83                                  5    R.sup.1 =R.sup.3 =Cl; R.sup.2 =R.sup.4 =H                                                 194-197                                                                              C.sub.10 H.sub.5 Cl.sub.2 NO.sub.3                                                   cal                                                                              46.54                                                                            1.95                                                                             5.43                                                                 fnd                                                                              46.25                                                                            1.95                                                                             5.42                                  6    R.sup.1 =R.sup.3 =Br; R.sup.2 =R.sup.4 =H                                                 275-276 (dec)                                                                        C.sub.10 H.sub.5 Br.sub.2 NO.sub.3                                                   cal                                                                              34.62                                                                            1.45                                                                             4.04                                                                 fnd                                                                              34.75                                                                            1.26                                                                             4.16                                  7    R.sup.1 =R.sup.3 =F; R.sup.2 =R.sup.4 =H                                                  259-260                                                                              C.sub.10 H.sub.5 F.sub.2 NO.sub.3                     __________________________________________________________________________

                                      TABLE II                                    __________________________________________________________________________    .sup.1 H-NMR for 2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benz[b]azepines in        dmso-d.sub.6 (Formula I)                                                      Ex. No.                                                                            R.sup.i =                                                                __________________________________________________________________________    2    R.sup.1 =R.sup.3 =R.sup.4 =H; R.sup.2 =Cl                                                 11.70(s, 1H, N H), 10.77(brs, 1H, O H) 7.98(d, 1H,                            J.sub.meta =2.6                                                               Hz), 7.72(dd, 1H, J.sub.ortho =8.8 Hz, J.sub.meta =2.6                        Hz), 7.5(d, 1H,                                                               J.sub.ortho =8.8 Hz), 6.44(s, 1H).                           3    R.sup.1 =R.sup.2 =R.sup.4 =H; R.sup.3 =Br                                                 11.64(s, 1H, N H), 10.8(brs, 1H, O H), 7.95(d, 1H,                            J.sub.ortho =8.67), 7.71(d, 1H, J.sub.meta =1.65 Hz)                          7.43(dd, 1H,                                                                  J.sub.ortho =8.67 Hz, J.sub.meta =1.65 Hz), 6.43(s, 1H)      4    R.sup.1 =R.sup.2 =R.sup.4 =H; R.sup.3 =F                                                  11.69(s, 1H, N H), 10.82(brs, 1H, O H), 8.11(dd, 1H),                         7.27                                                                          (dd, 1H), 7.14(m, 1H), 6.44(s, 1H)                           5    R.sup.1 =R.sup.3 =Cl; R.sup.2 =R.sup.4 =H                                                 11.43(s, 1H, N H), 10.84(brs, 1H, O H), 7.54(d, 1H,                           J.sub.meta =1.87                                                              Hz), 7.42(d, 1H, J.sub.meta =1.87 Hz), 6.37(s, 1H)           6    R.sup.1 =R.sup.3 =Br; R2=R.sup.4 =H                                                       11.37(s, 1H, N H), 10.83(s, 1H, O H), 7.79(d, 1H,                             J.sub.meta =1.1                                                               Hz), 7.58(d, 1H, J.sub.meta =1.1 Hz), 6.35(s, 1H)            7    R.sup.1 =R.sup.3 =F; R.sup.2 =R.sup.4 =H                                                  11.53(s, 1H, N H), 10.8(brs, 1H, O H), 7.15(t, 1H),                           7.02(d,                                                                       1H, J.sub.HFortho =10.6 Hz), 6.28(s, 1H)                     __________________________________________________________________________

                                      TABLE III                                   __________________________________________________________________________    .sup.1 H-NMR for 2,5-dihydro-2,5-dioxo-3-methoxy-1H-benz[b]azepine in         dmso-d.sub.6                                                                  (Formula II, R.sup.5 =CH.sub.3)                                                                Method of                                                    Ex. No.                                                                            R.sup.i =   Prep                                                         __________________________________________________________________________    2a   R.sup.1 =R.sup.3 =R.sup.4 =H; R.sup.2 =Cl                                                 A     11.47(s, 1H, N H) 7.88(d, 1H, J.sub.meta =2.6Hz),                             7.69(dd,                                                                      H, J.sub.ortho =8.8 Hz, J.sub.meta =2.6Hz),                                   7.44(d, 1H, J.sub.ortho =8.8                                                  Hz), 6.38(s, 1H), 3.82(s, 3H).                         3a   R.sup.1 =R.sup.2 =R.sup.4 =H; R.sup.3 =Br                                                 B     11.09(s, 1H, N H) 7.78(d, 1H, J.sub.ortho =8.53                               Hz), 7.50                                                                     (d, 1H, J.sub.meta =1.65 Hz), 7.24(dd, 1H,                                    J.sub.ortho =8.53 Hz,                                                         J.sub.meta =1.65 Hz), 6.24(s, 1H) 3.76(s, 3H).         4a   R.sup.1 =R.sup.2 =R.sup.4 =H; R.sup.3 =F                                                  B     8.06(dd, 1H), 7.23(dd, 1H), 7.11(m, 1H) 6.36(s,                               1H), 3.81(s, 3H).                                      5a   R.sup.1 =R.sup.3 =Cl; R.sup.2 =R.sup.4 =H                                                 B     11.28(s, 1H, N H), 7.54(s, 1H), 7.36(s, 1H),                                  6.44(s,                                                                       1H), 3.75(s, 3H).                                      6a   R.sup.1 =R.sup.3 =Br; R.sup.2 =R.sup.4 =H                                                 B     11.22(s, 1H, N H), 7.79(d, 1H, J.sub.meta =1.7 Hz)                            7.54(d,                                                                       1H, J.sub.meta =1.7 Hz), 6.43(s, 1H), 3.26(s,                                 3H).                                                   7a   R.sup.1 =R.sup.3 =F; R.sup.2 =R.sup.4 =H                                                  B     11.39(brs, H, N H), 7.18(m, 1H), 6.19(dd, 1H,                                 J.sub.HFortho =10.5 Hz, J.sub.meta =2.2 Hz),                                  6.35(s, 1H), 3.76(s,                                                          1H).                                                   __________________________________________________________________________

                                      TABLE IV                                    __________________________________________________________________________    .sup.1 H-NMR for 2-methoxy-1,4-naphthoquinone in dmso-d.sub.6 (Formula        III, R.sup.5 =CH.sub.3)                                                       Ex. No.                                                                            R.sup.i =                                                                __________________________________________________________________________    2b   R.sup.1 =R.sup.3 =R.sup.4 =H; R.sup.2 =Cl                                                 8.08(d, 1H, J.sub.ortho =8.0 Hz), 8.06(d, 1H, J.sub.meta                      =2.1 Hz) 7.67                                                                 (dd, 1H, J.sub.ortho =8.0 Hz, J.sub.meta =2.1 Hz),                            6.19(s, 1H), 3.92(s,                                                          3H).                                                         3b   R.sup.1 =R.sup.2 =R.sup.4 =H; R.sup.3 =Br                                                 8.10(d, 1H, J.sub.meta =1.92 Hz), 8.06(dd, 1H,                                J.sub.ortho =8.26 Hz,                                                         J.sub.meta =1.92 Hz), 7.91(d, 1H, J.sub.ortho =8.26 Hz),                      6.39(s, 1H), 3.9                                                              (s, 3H)                                                      4b   R.sup.1 =R.sup.2 =R.sup.4 =H; R.sup.3 =F                                                  8.04(m, 1H), 7.72(m, 2H), 6.37(s, 1H), 3.87(s, 3H)           5b   R.sup.1 =R.sup.3 =Cl; R.sup.2 =R.sup.4 =H                                                 8.10(d, 1H, J.sub.meta =2.2 Hz), 7.97(d, 1H, J.sub.meta                       =2.2 Hz), 6.37(s,                                                             1H), 3.86(s, 3H)                                             6b   R.sup.1 =R.sup.3 =Br; R.sup.2 =R.sup.4 =H                                                 8.30(d, 1H, J.sub.meta =1.9 Hz), 8.16(d, 1H, J.sub.meta                       =1.9 Hz), 6.20(s,                                                             1H), 3.90(s, 3H)                                             __________________________________________________________________________

                                      TABLE V                                     __________________________________________________________________________    .sup.1 H-NMR for 2-hydroxy-1,4-naphthoquinone in dmso-d.sub.6 (Formula        IV)                                                                           Ex. No.                                                                            R.sup.i =                                                                __________________________________________________________________________    2c   R.sup.1 =R.sup.3 =R.sup.4 =H; R.sup.2 =Cl                                                 8.08(d, 1H, J.sub.meta =2.3 Hz), 8.07(d, 1H, J.sub.ortho                      =7.9 Hz), 7.68                                                                (dd, 1H, J.sub.ortho =7.9 Hz, J.sub.meta =2.3 Hz), 7.37                       (brs, 1H,  OH), 6.38                                                          (s, 1H).                                                      3c* R.sup.1 =R.sup.2 =R.sup.4 =H; R.sup.3 =Br                                                 8.08(d, 1H, J.sub.meta =1.89 Hz), 8.02(dd, 1H,                                J.sub.ortho =8.25 Hz,                                                         J.sub.meta =1.89 Hz), 7.87(d, 1H, J.sub.ortho =8.7),                          6.22(s, 1H)                                                  4c   R.sup.1 =R.sup.2 =R.sup.4 =H; R.sup.3 =F                                                  8.0(m, 1H), 7.68(m, 2H), 6.17(s, 1H)                         5c   R.sup.1 =R.sup.3 =Cl; R.sup.2 =R.sup.4 =H                                                 8.09(d, 1H, J.sub.meta =2.2 Hz), 7.8(d, 1H, J.sub.meta                        =2.2 Hz), 7.07(s,                                                             1H,  OH), 6.38(s, 1H)                                        6c   R.sup.1 =R.sup.3 =Br; R.sup.2 =R.sup.4 =H                                                 8.29(d, 1H, J.sub.meta =2.0 Hz), 8.21(d, 1H, J.sub.meta                       =2.0 Hz), 7.1(s,                                                              1H,  OH), 6.4(s, 1H)                                         __________________________________________________________________________     *TFA-d.sub.1 added to dmsod.sub.6                                        

                                      TABLE VI                                    __________________________________________________________________________    .sup.1 H-NMR for 1-tetralones in CDCl.sub.3 (Formula V)                       Ex. No.                                                                            R.sup.i =                                                                __________________________________________________________________________    3d   R.sup.1 =R.sup.2 =R.sup.4 =H; R.sup.3 =Br                                                 7.92(d, 1H, J.sub.meta =2.26 Hz), 7.73(dd, 1H,                                J.sub.ortho =8.16 Hz,                                                         J.sub.meta =2.26 Hz), 7.34 (d, 1H, J.sub.ortho =8.16                          Hz), 2.91(t, 2H,                                                              J.sub.H34 =6.01 Hz), 2.62(t, 2H, 6.16 Hz), 2.04(m, 2H)       4d   R.sup.1 =R.sup.2 =R.sup.4 =H; R.sup.3 F                                                   7.54(m, 1H), 7.42(m, 2H), 2.93(t, 2H, J.sub.H34 =5.98                         Hz), 2.61                                                                     (t, 2H, J.sub.H23 =6.19 Hz), 2.04(m, 2H)                     __________________________________________________________________________

                                      TABLE VII                                   __________________________________________________________________________    .sup.1 H-NMR for 2-tetralones in CDCl.sub.3 (Formula Va)                      Ex. No.                                                                            R.sub.i =                                                                __________________________________________________________________________    5d   R.sup.1 =R.sup.3 =Cl; R.sup.2 =R.sup.4 =H                                                 7.32(d, 1H J.sub.meta =2.0Hz), 7.05(d, 2H, J.sub.meta                         =2.0 Hz), 3.57(s,                                                             2H), 3.19(t, 2H, J.sub.H34 =6.8 Hz), 2.56(t, 2H,                              J.sub.H34 =6.8 Hz)                                           6d   R.sup.1 =R.sup.3 =Br; R.sup.2 =R.sup.4 =H                                                 7.65(d, 1H, J.sub.meta =1.9 Hz), 7.24(d, 1H, J=1.9 Hz),                       3.57(s,                                                                       1H), 3.18(t, 2H, J.sub.H34 =6.7 Hz), 2.56(t, 2H,                              J.sub.H34 =6.7 Hz)                                           __________________________________________________________________________     ##STR1##

What is claimed is:
 1. A method of making a compound of formula I, or apharmaceutically acceptable salt thereof,wherein: R¹, R², R³ and R⁴ areindependently selected from:hydrogen, (1-3C)perfluoroalkyl, halo, nitroand cyano;which is characterized by reacting a compound of formula II:##STR2## wherein R¹, R², R³ and R⁴ are as defined above and R⁵ is a(1-5C)alkyl group, with a boron trihalide; and thereafter, when apharmaceutically acceptable salt is desired, reacting a compound offormula I with a suitable base affording a physiologically acceptablecation.
 2. A method according to claim 1 wherein:R¹, R², R³, and R⁴ areindependently selected from hydrogen, trifluoromethyl, pentafluoroethyl,heptafluoropropyl, and halo; and R⁵ is selected from methyl, ethyl,propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, and neopentyl. 3.A method according to claim 2 wherein:R¹, R², R³, and R⁴ areindependently selected from hydrogen, trifluoromethyl and halo; and R⁵is selected from methyl, ethyl, and propyl.
 4. A method of making acompound of formula II ##STR3## wherein: R¹, R², R³ and R⁴ areindependently selected from:hydrogen, (1-3C)perfluoroalkyl, halo, nitroand cyano; and R⁵ is a (1-5C)alkyl group;which is characterized byreacting a corresponding alkyl enol ether of formula III: ##STR4## withsodium azide in neat trifluoromethanesulfonic acid or concentratedsulfuric acid.
 5. A method according to claim 4 wherein:R¹, R², R³, andR⁴ are independently selected from hydrogen, trifluoromethyl,pentafluoroethyl, heptafluoropropyl, and halo; and R⁵ is selected frommethyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl,and neopentyl.
 6. A method according to claim 5 wherein:R¹, R², R³, andR⁴ are independently selected from hydrogen, trifluoromethyl and halo;and R⁵ is selected from methyl, ethyl, and propyl.